α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are a major class of ionotropic glutamate receptors that mediate the majority of fast excitatory synaptic transmission in the mammalian brain (Ozawa et al., Prog Neurobiol. 54(5): 581-618, 1998). The interdependency between AMPARs and N-methy-D-aspartate receptors (NMDARs) makes AMPARs a promising target for therapeutic intervention of NMDAR-mediated glutamatergic hypofunction. AMPAR activation is essential for NMDAR neurotransmission since the activation of AMPARs induces the depolarization of postsynaptic membranes, which relieves the Mg2+ block of the NMDAR channels (Lynch, Nat Neurosci 5 Suppl:1035-1038, 2002), and in turn enhances synaptic efficacy and augments glutamatergic neurotransmission (Arai et al., Neuroscience 123(4): 1011-1024, 2004). Moreover, NMDAR activation is essential for the recruitment of AMPA receptors to the membrane at activated synaptic sites (Sun et al., J Neurosci 25(32): 7342-7351, 2005). Direct activation of glutamate receptors by agonists to correct glutamatergic hypofunction increases the risk of excitotoxicity and additional neuronal damage. AMPAR positive allosteric modulators (PAMs) do not activate the receptor directly, but have been shown to increase receptor affinity for agonist (Arai et al., Neuroreport. 7(13):2211-5, 1996), reduce receptor desensitization and deactivation (Granger et al., Synapse 15(4): 326-329, 1993; Arai et al, Mol Pharmacol 58(4):802-13, 2000; Lynch and Gall, Trends Neurosci 29(10): 554-562, 2006), and enhance the induction of LTP both in vitro (Arai et al, Neuroreport. 7(13):2211-5, 1996) and in vivo (Staubli et al., PNAS 91 (23):11158-62, 1994). AMPAR PAMs also improve performance in a radial arm maze task assessing spatial working memory (O'Neill et al., Curr Drug Targets CNS Neurol Disord 3(3): 181-194, 2004; Quirk and Nisenbaum, CNS Drug Rev 8(3): 255-282, 2002), and robustly ameliorate ketamine-induced impairment of working memory (Roberts et al., Behav Brain Res 212(1): 41-48, 2010). Thus, discovery of new AMPAR PAMs aimed at correcting NMDAR-mediated glutamatergic hypofunction is needed to moderate or prevent situations associated with diminished NMDAR function. Therefore, bivalent AMPAR PAMs can be used as therapeutics for cognitive abnormalities involving glutamatergic hypofunction including schizophrenia, Alzheimer's disease, Parkinson's disease, addiction, and attention deficit hyperactivity disorder (ADHD).
AMPARs consist of a family of tetrameric receptors arising from four genes, each of which encodes a distinct receptor subunit (GluA1-4), each of which can undergo alternative splicing of a 38 amino acid sequence in the extracellular region just before the fourth membrane spanning domain M4 resulting in so called “flip” and “flop” splice variants (Ward et al., Br J Pharmacol 160(2): 181-190, 2010). It was recently revealed that the binding site for allosteric activators at the dimer interface actually consists of a large surface with several subsites (Ahmed et al., J Med Chem 53(5):2197-2203, 2010). This rather large surface with non-overlapping subsites suggests a means by which agonist affinity can be increased, that is, by generating bivalent or even multivalent compounds that can interact with different subsites.